ALBERT

Description: Multicentric Castleman’s disease (MCD) is a rare, lymphoproliferative disorder with high morbidity. MCD signs and symptoms are driven by dysregulated interleukin (IL)-6 production. Preliminary data suggest efficacy of siltuximab, a chimeric mAb against human IL-6, in MCD patients (van Rhee et al. J Clin Oncol 2010;28:3701-8). We evaluated the efficacy and safety of siltuximab in patients with symptomatic, measurable, HIV- and HHV-8-negative MCD in a phase 2, randomized, double-blind, controlled, multicenter study. Patients could be newly diagnosed/pre-treated and on stable, low-dose corticosteroids. Patients were randomly assigned 2:1 to siltuximab 11 mg/kg or placebo given by 1-h IV infusion q3w. All patients also received best supportive care to manage MCD symptoms. Patients received study agent until protocol-defined treatment failure, after which patients randomized to placebo could cross over to unblinded siltuximab. Primary analysis occurred after the last treated patient completed assessments at 48 wks. Primary endpoint was durable tumor and symptomatic response defined as PR or CR (Cheson criteria) by independent review and improvement/stabilization in MCD-related symptoms for ≥18 wks. Secondary endpoints included additional predefined efficacy measures and safety. 79 patients were randomized and treated with siltuximab (n=53) or placebo (n=26) from Feb 2010 to Feb 2013. Treatment arms were well balanced. Median age was 48 yrs, 48% were Asian, 39% were white, 66% were male, 30% were on corticosteroids, and 58% had prior systemic therapy. Patients had mixed (44%), hyaline vascular (33%), or plasmacytic (23%) histologic subtypes by pre-randomization central pathology review. Baseline MCD symptoms included fatigue (86%), malaise (61%), night sweats (52%), peripheral sensory neuropathy (38%), anorexia and pruritus (37% each). Median treatment duration was 375 vs. 152 d with siltuximab vs. placebo, with 64% vs. 27% completing 48 wks of treatment. A higher percentage of durable tumor and symptomatic response was observed with siltuximab compared with placebo (34% (1 CR, 17 PR) vs. 0%; p=0.0012). Investigator-reported response provided consistent conclusions. Median duration of tumor and symptomatic response in siltuximab-treated patients of 340 d indicates prolonged disease control. Tumor response rate by central radiology review was 38% vs. 4% (p=0.0022). Median time to treatment failure was not reached vs. 134 d (p=0.0084). Median time to next treatment was not reached vs. 280 d (p=0.0013). Durable symptomatic response rate was 57% vs. 19% (p=0.0018), including complete symptom resolution in 25% vs. 0% (p=0.0037). Hb improvement by ≥15 g/L at wk 13 was seen in 61% vs. 0% anemic patients (p=0.0002). Sustained decreases in CRP (a marker of IL-6 bioactivity), ESR, and fibrinogen, and increase in albumin were seen with siltuximab. 13 of 26 patients on placebo crossed over to siltuximab. The safety profile as defined by frequencies of treatment-emergent AEs was similar between siltuximab and placebo despite the 〉2x longer treatment duration with siltuximab: gr ≥3 AEs 47% vs. 54%, SAEs 23% vs. 19%, AEs leading to discontinuation 23% vs. 38% (mostly due to PD), AEs leading to treatment interruption 28% vs. 19%. Infusion reactions with siltuximab were infrequent (8%) and low grade, except for 1 anaphylactic reaction that led to treatment discontinuation. Gr ≥3 AEs frequently reported with siltuximab were fatigue (9%); night sweats (8%); and hyperkalemia, hyperuricemia, localized edema, hyperhidrosis, neutropenia, thrombocytopenia, hypertension, and weight increased (4% each). Gr ≥3 AEs reasonably related to siltuximab reported in 〉1 patient were neutropenia and thrombocytopenia (4% each). 3 (6%) patients had SAEs reasonably related to siltuximab. 2 (4%) patients in siltuximab died due to PD after treatment discontinuation. 4 (15%) noncrossover patients in placebo died (1 AE, 3 PD). This is the first randomized study in MCD. The efficacy of siltuximab in MCD patients was demonstrated by durable tumor and symptom response, and clinical benefit was confirmed by marked improvement of time to treatment failure, MCD-related symptoms, Hb levels, and sustained reduction in inflammatory markers. In conjunction with the tolerable safety profile in this population, this study provides compelling evidence that siltuximab should be considered a new treatment of choice for MCD patients. Disclosures: Wong: Roche: Research Funding; MSD: Research Funding; Johnson & Johnson: Research Funding; Bayer: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biogen-Idec: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Baxter: Research Funding; Amgen: Research Funding; Alexion: Honoraria. Casper:St. Jude Children's Hospital and Research Center: Membership on an entity’s Board of Directors or advisory committees; Hutchinson Cancer Research Institute--Uganda: Membership on an entity’s Board of Directors or advisory committees; Up-To-Date: Royalties Patents & Royalties; National Institutes of Health: Research Funding; Janssen Research & Development: Consultancy, Research Funding. Munshi:Janssen Research & Development: Membership on an entity’s Board of Directors or advisory committees. Fosså:Janssen Research & Development: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Simpson:Janssen Research & Development: Honoraria. Goh:Gilead Sciences, Inc: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Janssen Pharmaceuticals Inc: Research Funding; Novartis Pte Ltd: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Hospira, Inc: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Cavet:Janssen Research & Development: Research Funding. Bandekar:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Rothman:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Puchalski:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Chaturvedi:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. van de Velde:Johnson & Johnson: Equity Ownership; Janssen Research & Development: Employment. Vermeulen:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. van Rhee:Janssen Research & Development: Research Funding.

Description: Background: ABL001 is a potent, specific BCR-ABL inhibitor in development for the treatment of patients with CML and Ph+ ALL. ABL001 binds a pocket on the BCR-ABL kinase domain normally occupied by the autoregulatory myristoylated N-terminus of ABL1, which is lost upon fusion with BCR. ABL001 was designed to inhibit BCR-ABL in a non-ATP-competitive manner to maintain activity against BCR-ABL mutations that confer resistance to TKIs. Preclinically, combined with ATP-competitive TKIs, ABL001 eliminates early leukemic progenitors and diminishes emergence of resistant clones. Methods: Patients with CML-CP, -AP, or -BP with failure of ≥ 2 prior TKIs and Ph+ ALL patients with failure of ≥ 1 prior TKI due to resistance or intolerance were enrolled in this first-in-human, multicenter, open-label phase 1 dose-escalation study (CABL001X2101). Escalating doses of single-agent ABL001 were administered orally on continuous twice-daily (BID) or once-daily (QD) schedules or in combination with imatinib, nilotinib, or dasatinib. Therapy continued until disease progression, unacceptable toxicity, consent withdrawal, or death. Primary objectives were to estimate the maximum tolerated dose (MTD) of ABL001 administered as single agent or combined with TKIs. Secondary objectives included safety, preliminary efficacy, and pharmacokinetics of ABL001 alone and combined with TKIs. Dose escalation followed a Bayesian logistic regression model based on dose-limiting toxicities (DLTs) in cycle 1. Results: At data cutoff, 101 CML and Ph+ ALL patients had received ABL001 as either single agent or in combination. 67 CML and 6 Ph+ ALL patients have been treated at single-agent BID doses: 10 mg (n = 1), 20 mg (n = 14), 40 mg (n = 30), 80 mg (n = 14), 150 mg (n = 9), 200 mg (n = 5), with MTD not reached. A dose of 40 mg BID has been recommended for CML-CP patients. 19 CML patients have been treated with single-agent QD doses: 80 mg (n = 3), 120 mg (n = 10), 200 mg (n = 5), with MTD not yet reached. 9 CML patients have been treated in combination with TKIs with dose escalation ongoing. Median age was 55 y (range, 23-79 y). Most patients (98%) had baseline ECOG status 0-1. Patients were heavily pretreated; 65 (65%) had received 〉 2 prior TKIs. 70 patients were resistant to their last TKI. In 84 patients, treatment is ongoing at doses 20-200 mg BID or QD and at respective combination doses, with 17 patients discontinued (disease progression [n = 6], AEs [n = 7], consent withdrawal [n = 4]). Median duration of exposure is 34 wk (range, 0-98 wk). ABL001 pharmacokinetics was dose-proportional with minimal accumulation across dose and time. There were 5 DLTs: 2 Gr 3 lipase elevations (40 mg BID and 200 mg QD), 1 Gr 2 arthralgia (80 mg BID), 1 acute coronary syndrome (150 mg BID), and 1 Gr 3 bronchospasm (200 mg BID). 3 cases of Gr 2 acute pancreatitis occurred in cycle 5 at doses ≥ 80 mg BID. The majority of AEs regardless of study drug relationship were grade 1/2. Most common grade 3/4 AEs suspected related to ABL001 were lipase increase (8%), thrombocytopenia (7%), anemia (5%), and neutropenia (4%). 1 non-study drug-related death due to multiorgan failure occurred. 55 patients (10-200 mg BID) on therapy for ≥ 3 months had efficacy assessments. 7/9 patients in cytogenetic relapse (〉 35% Ph+ metaphases at baseline) achieved CCyR by 6 months, with all 7 maintaining CCyR by 12 months. 13 of 55 (23.6%), 16 of 37 (43.2%), and 20 of 55 (57.1%) patients achieved or maintained MMR by 3, 6, and 12 months, respectively. Of 47 patients with baseline BCR-ABL 〉 0.1 % IS, 6 of 47 (12.8%), 9 of 30 (30%), and 13 of 28 (46.4%) patients achieved MMR by 3, 6 and 12 months, respectively. Of 32 patients with baseline BCR-ABL ≤ 10 % IS, 4 (12.5%), 9 (28%), and 11 (34%) achieved ≥ 1-log reduction of BCR-ABL % IS by 3, 6 and 9 months, respectively, with all maintained at 12 months. 17/20 patients who achieved MMR have maintained it. Clinical activity was seen in multiple TKI-resistant mutations. 7 patients with T3151I were enrolled: 3 achieved CCyR (1 relapse by 6 months) and 1 maintained baseline MMR at median follow-up of 8 months. Only 1/6 relapsed patients had detectable myristoyl-pocket mutations (V468F, I502L). Conclusion: ABL001 appears well tolerated to date and exhibits significant and durable activity in a heavily pretreated subgroup of CML patients. 40 mg BID has been recommended for CML-CP patients. Phase 1 accrual is ongoing for CML patients on QD or combination therapy, with T3151I mutations, and Ph+ ALL patients. Disclosures Hughes: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Goh:Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ottmann:Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Fusion Pharma: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Ariad: Consultancy, Honoraria. Minami:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Rea:Ariad: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Lang:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mauro:Ariad: Consultancy; Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy. DeAngelo:Novartis: Consultancy; Ariad: Consultancy; Incyte: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Baxter: Consultancy; Pfizer: Consultancy. Talpaz:Incyte Corporation: Other: Travel expense reimbursement, Research Funding; Novartis: Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Pfizer: Consultancy, Other: travel accomodation expenses, Research Funding. Hochhaus:Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Ariad: Research Funding. Breccia:Pfizer: Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria; Novartis: Consultancy, Honoraria. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Heinrich:MolecularMD: Consultancy, Equity Ownership; Novartis: Consultancy, Honoraria, Patents & Royalties; Ariad: Consultancy. Janssen:Pfizer: Honoraria; Novartis: Research Funding; Ariad: Honoraria; BMS: Honoraria. Steegmann:Pfizer: Honoraria, Other: research funding for the Spanish CML group; Novartis: Honoraria, Other: research funding for the Spanish CML group; BMS: Honoraria, Other: Research funding for the Spanish CML Group; Ariad: Honoraria, Other: Research funding for the Spanish CML Group. Mahon:Ariad: Honoraria; Pfizer: Honoraria; Novartis: Honoraria, Research Funding; BMS: Honoraria. Duan:Novartis Institutes for Biomedical Research, Inc.: Employment. Iyer:Novartis Institutes for Biomedical Research, Inc.: Employment. Hynds:Novartis Institutes for Biomedical Research, Inc.: Employment. Vanasse:Novartis Institutes for Biomedical Research, Inc.: Employment. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; II-Yang: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Description: Despite being developed in eras when standard treatments for Chronic Phase Chronic Myeloid Leukemia (CP-CML) differ, Sokal, Hasford, and European Treatment and Outcome Study (EUTOS) scores each remain in use for predicting survival outcomes. The European LeukemiaNet (ELN) 2013 guidelines state that no one score is superior to the other. Furthermore, no studies have examined how a combination of scores may improve prognostic value. This retrospective, multicenter study compared the scores, individually and in combination, on predicting Overall Survival (OS), Progression-Free Survival (PFS) and Event-Free Survival (EFS) for CP-CML patients in Singapore General Hospital (Singapore), Seoul St. Mary's Hospital (South Korea) and Chang Gung Memorial Hospital (Taiwan). A total of 1222 newly diagnosed CP-CML patients (2013 ELN criteria) between July 1998 to December 2013 with follow-up period ≥18 months were reviewed. OS was defined as death from any cause, PFS was defined as transformation to accelerated or blastic phase and CML-related death. EFS was defined as failure according to the 2009 ELN criteria, treatment changes, progression, and death. Log likelihood ratio (LR) test of nested models was performed to compare dual combination scores with its individual components. Adequacy index was used to quantify the percentage of variation explained by each pair of scores. Harrell's c-index was also calculated to evaluate the predictive ability of the scores. Linear contrast test was used to further stratify the individual risk groups in dual combination scores. For OS, comparison of Sokal + EUTOS vs. EUTOS (LR 40.44 vs. 0.49) or Sokal + Hasford vs. Hasford (LR 31.78 vs. 11.81) showed that the combined model was significantly better than the individual models alone (p-valueEUTOS, which are supported by Harrell's c-indices of 0.665, 0.591, 0.514, respectively. Similar predictive ability order for individual scores were also drawn for EFS (refer to table 1). For PFS, comparison of Sokal + Hasford vs. Hasford showed the combined model was significantly better (LR 34.05 vs. 12.32, p-valueHasford, which is in agreement with the c-indices (0.620 vs. 0.569, respectively). Comparison of Sokal + EUTOS to either Sokal or EUTOS alone was both significantly better (LR 42.50 vs. 35.76, LR 42.50 vs. 20.33, respectively; p-value

Description: Abstract 2883 Background: Inotuzumab ozogamicin (CMC-544) is a humanized anti-CD22 antibody conjugated to calicheamicin, a cytotoxic agent. CMC-544 targets CD22, which is expressed in the majority of B-cell non-Hodgkin lymphomas (NHL). CMC-544 alone and in combination with rituximab has demonstrated efficacy and tolerability in relapsed/refractory NHL patients including diffuse large B-cell lymphoma (DLBCL) patients who were ineligible for high-dose therapy and autologous stem cell transplant (HDT-aSCT). This trial is evaluating the safety and preliminary efficacy of CMC-544 plus rituximab (CMC-544+R) followed by HDT-aSCT. Objectives: Assess the safety and activity of CMC-544+R prior to HDT-aSCT in relapsed/refractory DLBCL patients using overall response rate (ORR), rate of successful peripheral blood stem cell (PBSC) collection, and aSCT rate as endpoints. Patients: Patients are eligible for this ongoing trial if they have CD20+/CD22+ B-cell DLBCL, have received 1 or 2 therapies, have at least 2 adverse prognostic factors (prior rituximab exposure, early (1), and are judged eligible for HDT-aSCT. Rituximab (375 mg/m2) is given on day 1, then CMC-544 (1.8 mg/m2) on day 2 every 21 days for up to 6 cycles; PBSC mobilization with G-CSF (+/− plerixafor injection [Mozobil®]) begins no earlier than day 8 of cycle 2. Chemo-primed mobilization (with cyclophosphamide [C] or etoposide [E]) is allowed if insufficient PBSCs are collected by G-CSF and is initiated only after disease response is observed. Patients responding to CMC-544+R and with sufficient PBSCs (〉2×106 CD34+ cells/kg) proceed to HDT-aSCT. Results: To date, 34 patients have been treated with CMC-544+R. Median age is 62 y (range: 19–75); 74% male; 50% had 1 prior chemotherapy regimen, 38% had 2, and 9% had ≥ 3. Most common adverse events during CMC-544+R treatment were: thrombocytopenia (38%), neutropenia (21%), lymphopenia (21%), nausea (27%), fatigue (29%), and increased aspartate aminotransferase (21%). Three deaths have been reported: 2 due to disease progression at days 76 and 126 after last dose of CMC-544; and 1 after HDT-aSCT. There have been no reports of veno-occlusive disease. To date, 19 patients have postbaseline disease assessment(s), with adverse prognostic factors as follows: 100% prior treatment with rituximab; 79% with sIPI 〉1 (range, 2–4); 37% had no response to their most recent prior therapy, 53% responded but had early relapse or required initiation of new anti-cancer treatment (CMC-544+R) 12 months). Additionally, all had prior treatment with both anthracyclines and alkylating agents. For these 19 patients (each with ≥ 2 adverse prognostic factors) and who received a median of 2 cycles, a best ORR of 21% was observed (2 complete and 2 partial responses); 26% showed stable disease, and 53% had disease progression. Of the 4 responders, 1 had no response to prior R-ICE, 1 had early relapse (~ 6 months) after prior R-CHOP, 1 relapsed 12 months after prior aSCT, and 1 had a complete response to R-DHAP 5 years prior to study treatment. To date, 7 patients have had PBSC collections: of these, 5 had successful collections (3 with G-CSF plus plerixafor, 1 with G-CSF alone, 1 with G-CSF plus chemo-priming); 2 patients, receiving G-CSF alone, did not have successful collections. Three patients have had both a response to CMC-544+R and sufficient PBSCs allowing HDT-aSCT: 1 patient had successful carmustine/E/cytarabine/C (BEAC)-aSCT (neutrophil, platelet recovery 11 and 29 days after aSCT, respectively); 1 patient did not have complete platelet recovery after busulfan/E/melphalan (M)-aSCT with 4.35×106 CD34+ cells/kg (platelet levels were as low as 19,000/μL ~60 days after aSCT, and transfusions were required to sustain levels ≥20,000/μL); and 1 patient, a 74-y old male, expired 39 days after BEAM-aSCT from neutropenic sepsis with multiorgan failure. Conclusion: In this patient population, CMC-544+R has a safety profile similar as previously reported. The preliminary ORR observed is notable given the poor prognosis of these patients. Current results suggest that successful PBSC mobilizations following CMC-544+R are possible. Additional data from this ongoing trial will be helpful to further assess the safety and efficacy of CMC-544+R prior to HDT-aSCT. Disclosures: Goy: Allos Therapeutics: Consultancy, Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Goh:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Ciliag: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sweetenham:Pfizer: Research Funding. Powell:Pfizer: Employment, Equity Ownership. Sullivan:Pfizer: Employment, Equity Ownership. Vandendries:Pfizer Inc.: Employment, Equity Ownership. Gisselbrecht:Allos Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Description: Abstract 3056 Introduction: Multiple myeloma (MM) is clinically heterogeneous and risk stratification is vital for prognostication and informing treatment decisions. As bortezomib is able to overcome several adverse features of MM, it has been incorporated into the induction algorithms of high-risk MM. We evaluate the survival data of MM patients managed in a single institution, overall, and with respect to treatment eras before (era 1) and after (era 2) the incorporation of bortezomib as frontline therapy for high-risk MM. Methods: From a comprehensive MM registry maintained in a tertiary institution, we study the survival data of 304 consecutive and previously untreated MM patients managed at our institution from 2000 to 2009. For induction therapy, transplant-eligible patients received. VAD chemotherapy from 2000 to 2004, and thalidomide/dexamethasone (thal/dex) combination from 2004 to 2009. Transplant-ineligible patients received VAD chemotherapy, thal/dex or melphalan/prednisolone (MP) combination from 2001 to 2004, and thal/dex or MP/thalidomide combination from 2004 to 2009. Patients 〈 65 years were eligible for high-dose therapy with autologous stem cell transplant (HDT/ASCT). Bortezomib became available for treatment of relapsed disease from 2004 and was incorporated into induction therapy in selected patients with high-risk MM from 2006. High-risk MM is defined by presence any adverse factors including stage III on the International Staging System (ISS), deletion 13, hypodiploidy, pseudo-diploidy or near-tetraploidy on metaphase karyotyping, or presence of deletion 17p, t(4;14) or t(14;16) on interphase florescence in-situ hybridization (FISH). As FISH was only available from 2004, the results of FISH will not be included in the survival analysis. Patient and disease characteristics, and survival data were evaluated overall, and with respect to treatment eras. Disease response was assessed by the IMWG criteria after induction treatment and after HDT/ASCT for transplant ineligible and eligible patients respectively. We applied multivariate Cox's regression modeling to determine what baseline parameters, along with the eventual induction response, significantly affected the OS in the respective eras. Results: The median age of all patients was 62 years. Overall, 35%, 40% and 25% of patients presented with ISS stages I, II and III respectively. Conventional karyotyping detected abnormalities in 49% (del 13 [17%], hypodiploidy [18%], hyperdiploidy [22%], pseudodiploidy [7%] and near tetradiploidy [2%]) of patients. Overall, the ISS, conventional cytogenetics, age (≤ or 〉 60 years), the presenting platelet count (≤ or 〉 140 × 109/L) and the induction response attained were discriminating of the overall survival (OS) (median= 5.2 yrs) on univariate analyses. Patients and disease characteristic and number of patients undergoing HDT/ASCT were comparable between the 2 eras. 33% of patients in era 1(N=182) were exposed to bortezomib predominantly in the relapse setting, while 52% (41% upfront, 59% during relapse) of patients were exposed to bortezomib (N=123) in era 2. Number of patients attaining ≥ very good partial response (VGPR) were significantly higher in era 2 compared with era 1 (48% vs 26%, p

Description: Background: ABL001 is a potent, specific BCR-ABL inhibitor in development for the treatment of patients with chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. ABL001 binds a pocket on the BCR-ABL kinase domain normally occupied by the myristoylated N terminus of ABL1, which serves an autoregulatory function subsequently lost upon fusion with BCR. ABL001 functionally mimics this autoregulatory role and restores negative regulation of kinase activity. In preclinical studies, ABL001 selectively inhibits the growth of BCR-ABL-positive cells, with activity noted against clinically observed TKI resistance mutations. ABL001 exhibits potent antitumor activity in KCL-22 xenografts, with evidence of complete tumor regression correlating with pSTAT5 inhibition. Animals receiving ABL001 and nilotinib in combination achieved sustained tumor regression without emergence of resistant disease even after treatment discontinuation. Methods: Patients with CML in chronic or accelerated phase with failure of ≥ 2 prior TKIs due to resistance or intolerance were enrolled on this first-in-human, multicenter, open-label phase 1 dose-escalation study (CABL001X2101). Escalating doses of single-agent ABL001 were administered orally on a continuous twice daily (BID) dosing schedule. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary objective was to estimate the maximum tolerated dose (MTD) of ABL001 administered as a single agent, orally, BID. Secondary objectives included safety, preliminary anti-CML activity, and pharmacokinetics of ABL001. Dose escalation followed a Bayesian logistic regression model based on dose-limiting toxicities (DLTs) occurring in cycle 1. Adverse events (AEs) were graded according to NCI-CTCAE v4.03. Efficacy analysis was based on hematologic, cytogenetic, and molecular assessments. Results: At data cutoff, 35 patients had been treated at the following BID doses: 10 mg (n = 1), 20 mg (n = 5), 40 mg (n = 12), 80 mg (n = 11), 150 mg (n = 6), and MTD has not yet been reached. Median age was 56 years (range, 23-74 years). Most patients (97%) had baseline Eastern Cooperative Oncology Group performance status 0-1. Patients were heavily pretreated; 20 (57%) had received ≥ 3 prior TKIs. In 30 patients, treatment is ongoing at doses 20-150 mg BID, with median duration of exposure of 20.9 weeks (range, 0-49.7 weeks), and 5 patients discontinued (disease progression [n = 1], AEs [n = 3], stem cell transplant [n = 1]). Preliminary data suggests ABL001 pharmacokinetics is dose-proportional with minimal accumulation across dose and time. There were 3 DLTs: 1 grade 3 lipase elevation and 1 grade 2 arthralgia at 40 mg BID and 1 acute coronary syndrome at 150 mg BID. In addition, 3 cases of grade 2 acute pancreatitis occurred in cycle 5 at doses ≥ 80 mg BID. The majority of AEs regardless of study drug relationship were grade 1/2. Most common grade 3/4 AEs were anemia (9%), thrombocytopenia (6%), neutropenia (6%), and lipase increase (6%). No deaths have occurred on study. 20 patients (10-80 mg) on therapy for ≥ 3 months had hematologic, cytogenetic, and molecular assessments. 17 patients were resistant to and 3 were intolerant of prior TKIs. Evidence of single agent activity was noted at doses ≥ 10 mg BID. All patients in complete hematologic (CHR) or complete cytogenetic (CCyR) response or with BCR-ABL ≤ 0.1 % IS at baseline have maintained responses. All 5 patients in hematologic relapse achieved CHR within 3 months. 9 of 11 TKI-resistant patients in cytogenetic relapse (〉 65% Ph+ metaphases at baseline) achieved a major cytogenetic response by 3 months, including 6 who achieved CCyR. Of 17 TKI-resistant patients with baseline BCR-ABL 〉 0.1 % IS, 11 achieved a ≥ 1-log reduction in BCR-ABL % IS and 5 achieved major molecular response by 5 months. Clinical activity was seen across TKI-resistant mutations, including Y253H and V299L. Only 1 patient in accelerated phase has relapsed on study, with relapse due to a mutation in the myristoyl pocket. Conclusion: ABL001 exhibits rapid dose-dependent antitumor activity and appears well tolerated to date in a heavily pretreated subgroup of patients with CML, providing proof of principle of the effectiveness of allosteric inhibition of the BCR-ABL kinase in the treatment of CML. The phase 1 study is ongoing in dose escalation. Disclosures Ottmann: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees. DeAngelo:Bristol Myers Squibb: Consultancy; Amgen: Consultancy; Ariad: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; Agios: Consultancy; Novartis: Consultancy. Goh:Roche: Honoraria; Janssen: Honoraria, Research Funding; Gilead Sciences: Honoraria; Sanofi: Honoraria; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria. Heinrich:Bristol-Myers Squibb: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Blueprint Pharmaceuticals: Consultancy; Ariad: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; MolecularMD: Consultancy, Equity Ownership, Research Funding. Hochhaus:ARIAD: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Hughes:ARIAD: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Mahon:ARIAD: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria. Mauro:Novartis Pharmaceutical Corporation: Consultancy, Research Funding; Ariad: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy. Minami:Novartis: Honoraria, Other: Member of IDMC , Research Funding. Rea:Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Ariad: Honoraria; Novartis: Honoraria. Steegmann:Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria, Research Funding. Chatterjee:Novartis Pharmaceuticals: Employment. Iyer:Novartis Pharmaceuticals: Employment, Equity Ownership. Martinez:Novartis Institute for Biomedical Research: Employment. Vanasse:Novartis Pharmaceuticals: Employment, Equity Ownership. Dong-Wook:ll-Yang: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Description: Introduction: Failure of hematopoietic stem cell (HSC) mobilization occurs in 5 to 30% patients planning for high dose chemotherapy and autologous HSC transplantation worldwide. It has adverse impact on patient outcomes and significantly increases health care burden. Data regarding HSC mobilization based on chemotherapy + granulocyte colony stimulating factor (G-CSF) in Asia are currently limited. Objective: The primary objective was to determine the safety and efficacy of HSC chemo-mobilization protocols in Asia for patients with non-Hodgkin lymphoma (NHL) or multiple myeloma (MM) planning for autologous HSCT. The secondary objective was to provide an estimate of the cost of chemo-mobilization in Asian countries Study Design: This was a multicenter, multinational retrospective observational study. Patients with NHL or MM undergoing chemo-mobilization for planned autologous HSCT between 1 Jan 2009 to 31 Dec 2012 in five Asian countries including Thailand, Singapore, Malaysia, Hong Kong and Taiwan, were retrospectively included in the study. Patient demographics, disease diagnoses, previous treatment history as well as complete blood counts prior to chemo-mobilization and apheresis, were collected. Results: A total of 526 patients (male/female = 207/219) were analyzed (diagnoses: NHL=257; MM=269). 160 patients were recruited from Thailand, 98 from Malaysia, 161 from Taiwan, 59 from Singapore and 48 from HK. Median age for the overall group was 53 years (range: 15-82). The most common mobilization regimen was cyclophosphamide + G-CSF; 235 (87.4%) in MM and 72 (28%) in NHL patients. 448 (85.2%) patients had reached at least HSC yield of 2 x 106CD 34+ cells/kg in 1 or 2 apheresis days. During chemo-mobilization, 108 (20.5%) patients were without negative clinical events (grade 3/4 neutropenia, febrile neutropenia, prolonged hospitalization, bone pain, fever, gastrointestinal, line infections or others). Grade 3/4 neutropenia and febrile neutropenia occurred in 401 (76.2%) and 72 (13.7%) patients, respectively. Median number of apheresis sessions was 2 (range: 1-5). Median cost of mobilization was 6,200USD (9,000-48,000). The respective median costs in USD (range) was; 3,500 (1,500-28,500) in Thailand, 6,900 (2,300-29,600) in Malaysia, 7,700 (3,400-48,000) in Taiwan and 9,200 (900-45,400) in Singapore. 436 (82.9%) patients proceeded to receive high dose chemotherapy and HSCT but 94 (17.87%) patients did not, due to insufficient HSC yield (n=26, 4.94 %), progression of disease (n=18, 3.42 %), patient not fit/ withdrawal from study (n=19, 3.61 %), patient expiry (n=11, 2.09 %) and other reasons (n=20, 3.80 %). Conclusion: Cyclophosphamide and G-CSF is the most common mobilization regimen used in Asian countries. Current chemo mobilization regimens are associated with a satisfactory rate of successful stem cell collection but with a high rate of significant toxicity. More than three-quarter of patients suffered from grade 3/4 toxicity during chemo-mobilization, however, only 20% of them had febrile neutropenia. Variations exist in the cost of chemo-mobilization in Asia, both among and within countries. Disclosures Goh: Novartis Pte Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen Pharmaceuticals Inc: Research Funding; Bristol-Myres Squibb: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hospira Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Background Relapsed/refractory PTCL and NKL after conventional chemotherapy carry a poor prognosis and there is currently no proven salvage treatment available. Numerous preclinical studies have demonstrated synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors. PAN inhibits the aggresome pathway of protein degradation, which is upregulated when the proteasome pathway is inhibited by BTZ. Primary end point of this phase II multi-center open-label clinical study (NCT00901147) is the objective response rate (ORR) according to the Revised Response Criteria (Cheson 2007) among eligible patients (pts) treated with this novel combination of BTZ and PAN. Secondary end points include the evaluation of the progression-free survival (PFS) and the assessment of the safety and tolerability of the combination. We report the final clinical results of our study exploring this novel combination. Methods Pts with histologically confirmed PTCL or NKL who failed or were refractory to 1 or more prior systemic therapy, and had measurable disease and ECOG performance status 0–2 were eligible. Pts were accrued according to a 2-stage Gehan design. Pts receive thrice weekly oral PAN (20 mg) and twice weekly BTZ (IV 1.3 mg/m2), both for 2 of 3 weeks for up to 8 cycles. CT scanning and/or FDG-PET were performed after every two cycles. Results: Among 25 pts enrolled, histologies included: angioimmunoblastic T-cell lymphoma (AITL) n=8, PTCL (unspecified) n=11, Anaplastic large cell lymphoma, ALK+ and ALK- n=1 and 2 respectively, NKL, nasal type n=2 and subcutaneous panniculitis-like T-cell lymphoma n=1. The median age was 59 (35-79) years, and 64% were male. Outcomes are available on 23 patients as 2 patients withdrew consent before any response assessment could be made. The ORR (CR+PR) was 43% (10/23) with 22% (5/23) attaining a CR. Median time to response was 6 weeks. Five pts (22%) had stable disease while 8 pts developed progressive disease (35%) while on study. Pts received a median of 2 prior therapies (range 1-4); 28% had prior autologous stem cell transplantation (SCT). Common treatment-related grade 3/4 adverse events included thrombocytopenia (68%), neutropenia (36%), diarrhoea (28%) and asthenia/fatigue (16%). Peripheral neuropathy of any grade was observed in 40%. 5 pts successfully underwent subsequent allogeneic SCT. Updated survival analysis will be presented. Conclusions The study regimen is generally well tolerated and shows encouraging activity across different T/NK-cell lymphomas. The novel combination could successfully serve as a bridge to allogeneic SCT for many transplant-eligible patients who have failed conventional chemotherapy. These results form the basis for further validation studies on proteasome and HDAC inhibition in PTCL or NKL. Ongoing correlative studies are designed to determine if the study regimen is more active in diseases with up-regulation of NF-kappa B activity or transcription factors/ co-regulators known to be modified by acetylation. Disclosures Goh: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jannsen Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Kim:Novartis, Celgene, Takeda: Research Funding. Tan:JANSEN: Honoraria, Research Funding; NOVARTIS: Research Funding.

Description: The optimal post-remission consolidation in Acute Myeloid Leukemia (AML) remains a topic of some debate, especially in the intermediate risk group of patients. We undertook a retrospective analysis of newly diagnosed AML patients treated in Singapore General Hospital from 1999 to 2012. Patients with M3 AML and patients who did not receive treatment of curative intent were excluded. 286 patients were identified for analysis, median age was 48 (range 15 to 79), ELN risk grouping: Favorable (FR) (n=84), Intermediate-1 (IR1) (n=120), Intermediate-2 (IR2) (n=57), and High risk (HR) (n=25). Post-remission therapy was administered as follows, 107 received high dose cytarabine (HiDAC) consolidation, 67 received autologous hematopoietic stem cell transplant (HCT), and 112 received allogeneic HSCT. Conditioning for allogeneic HCT was administered according to widely accepted protocols: bulsuphan and cyclophosphamide (Bu/Cy) for patients 50 years and younger while reduced intensity or non-myeloablative protocol was administered for older patients or the physically unfit. Patients for Autologous HCT were mobilized with VP16 and cytarabine and conditioned with Bu/Cy. HiDAC was administered at 3g/m2 q12h on days 1, 3 and 5; the dose was reduced to 1 to 1.5g/m2 for those above 60 years old, median number of HiDAC cycles was 4 (range 1 - 4). After a median follow up of 110 months, 5 year overall survival (OS) between patients who received HiDAC, autologous HCT and allogeneic HCT was 43.2 %, 63% and 48.3% (p =.04), 5 year leukemia free survival (LFS) was 40.3%, 61% and 43.2% and (p = .01). The apparent difference between autologous and allogeneic HSCT (p=.119) disappeared when we excluded HR patients, in which only 1 received autologous HSCT. However, the OS difference between autologous HSCT and HiDAC remained significant (p=.03). When patients were stratified according to ELN risk, OS and LFS were similar in FR patients regardless of consolidation modalities (p = .67 and p = .18) while IR1 and 2 patients receiving HiDAC had poorer outcomes when compared with autologous and allogeneic HSCT (OS: 26.9%, 57.6%, 54.1%; LFS: 23.4%, 56.3%, 45.9% respectively, p 〈 .0001 for OS and LFS), this remained significant when patients who did not complete at least 3 cycles of HiDAC consolidation were excluded (p = .02 for OS and LFS). In those who underwent autologous HSCT, predictors of better survival were age 〈 40 years (5yr OS 74.2% vs 56.7% p = .04, 5yr LFS 70% vs 56.7% p = .09), ELN favorable risk (5yr OS 80% vs 55% p = .03, 5 yr LFS 70% vs 55% p = .08) and bone marrow (BM) blast percentage of less than 70% in conjunction with a diagnostic white blood count (WBC) of less than 30 x 109 (5yr OS 75.7% vs 40% p = .007, 5yr LFS 70.9% vs 40% p = .01). On multivariate analysis, only BM blast of 〈 70% and diagnostic WBC of less than 30 x 109 remained predictive of OS (p = .048) and LFS (p = .049). Long term outcomes of patients who remained disease free 2 years post consolidation were excellent, with 84.5% alive and disease free 10 years after diagnosis. 4 (9.3%) patients relapsed in the HiDAC group, 6 (14.3%) in autologous HSCT and 2 (4%) in allogeneic HCT group. There is a tendency towards late AML relapse (〉 4 yrs) in patients receiving HiDAC and autologous HCT (4/43 and 4/42 respectively) compared with those receiving allogeneic HSCT 1/49, although the differences were not statistically significant (p = .36). 8 patients in both HiDAC and autologous HSCT group developed a secondary malignancy while 3 in the allogeneic HCT group had a second cancer. 10yr OS in those who were alive and disease free 2 years post consolidation was 88.7% in the HiDAC group, 82.6% in the autologous group and 85.6% in the allogeneic group. In conclusion autologous HCT remains a viable post-remission treatment modality for AML in first complete remission, with acceptable short and long term outcomes compared with allogeneic HCT and HiDAC consolidation. The benefit of autologous HCT appears to be most pronounced in the IR group and patients with low BM blast and WBC at diagnosis. We recommend that autologous HCT be considered in these groups of patients without a matched donor. Overall Survival for intermediate risk patients. P = 〈 0.001 Leukemia Free Survival for intermediate risk patients. P = 〈 0.001 Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.